DESCRIPTION (the applicant's description verbatim): Atrial fibrillation is a major cause of morbidity as well as of mortality due to stroke in the United States. Moreover, atrial fibrillation - once it occurs- tends to recur and to become persistent, such that most clinical interventions used remain palliative rather than curative. The goal of the proposed studies is to consider the mechanisms for the initiation of atrial fibrillation in a way that stresses early warnings of the likelihood of fibrillation and modalities for prevention. As such, we rely on the ECG and vectorcardiogram to study the P and Ta waves and the effects on these of altered atrial rate and activation, as the heart is paced at various rates and at various sites in a conscious canine model. We also consider the remodeling that occurs electrophysiologically with alterations in activation and rate in studies of intact animal and cellular electrophysiology, ion channels and gap junctions. We then proceed to the induction of atrial fibrillation, observing its evolution from non-sustained to sustained and the association of P and Ta wave changes, cellular electrophysiology, ion channels and gap junctions that occur with this sequence. Finally, in considering new modalities of prevention we use individual and combined approaches with an antiarrhythmic drug, an angiotensin II receptor-blocking drug and a Ca channel agonist to attempt to slow and/or reverse evolution of the substrate. Among the variables intensively studied are the rate-related changes in action potential characteristics in multicellular preparations, the role of Ca in determining these events, changes in inward (Na and Ca) and outward (K) currents that contribute to cardiac repolarization and the molecular determinants of gap junctional function. Finally, because of the role of age as an independent risk factor in the clinical expression of atrial fibrillation, and our preliminary data suggesting significant alterations in repolarizing currents with age, all studies are performed in adult and old animals. The significance of the work is in the attempt to utilize an understanding of mechanism in the design of methods for early identification of risk, and in the testing of modalities for prevention in an adult population and an aged population. Although cellular electrophysiologic and biophysical and molecular biological techniques are used the approach is not reductionist, but integrative, deliberately focused on synthesizing a mechanistic understanding of clinically-observed changes in P and Ta waves and their utilization in prediction and prevention of atrial fibrillation.